Identification of TIM-3/Gal-9 Autocrine Loop As a Novel Wnt-Ligands Independent Machinery for the Constitutive Activation of Canonical Wnt Pathway in AML-LSCs

We originally identified T-cell immunoglobulin mucin-3 (TIM-3) as a leukemic stem cells (LSCs)-specific surface molecule and a useful marker for discriminating LSCs from hematopoietic stem cells (HSCs). Furthermore, we recently identified an unique autocrine loop composed of TIM-3 and its ligand galectin-9 (Gal-9). This TIM-3/Gal-9 autocrine loop enhances self-renewal capacity of AML-LSCs and contributes to leukemia progression(Kikushige et al., Cell Stem Cell 2015).To clarify the molecular mechanism how TIM-3 signaling enhances stem cell properties of AML-LSCs, we performed shRNA-mediated knock-down(KD) of TIM-3 in KASUMI-3 (TIM-3+ AML cell line). As a result, TIM-3-KD significantly reduce the proliferation of KASUMI-3. To investigate how TIM-3-KD attenuated leukemia propagation, we compared gene expression profile of scramble-infected control and TIM-3-KD KASUMI-3 cells. Gene Set Enrichment Analysis (GSEA) revealed TIM-3-KD resulted in the significaltly attenuated expression of HSCs and LSCs-related genes (Eppert et al., Nature Med 2011) and canonical Wnt pathway-related genes (BioCarta). Since canonical Wnt pathway is known to regulate stem cell properties via inducing the nucleus accumulation ofβ-catenin in many types of stem cells including HSCs, we next examined the β-catenin level in TIM-3-KD-KASUMI-3 cells. Array scan analysis revealed that KD of TIM-3 significantly impaired the the nucleus accumulation of β-catenin in KASUMI-3 cells. In various types o...
Source: Blood - Category: Hematology Authors: Tags: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: Poster I Source Type: research